Worldwide, increasing number of women uses injectable contraceptives such as depot medroxy- progesterone acetate (DMPA) due to its ease of use and high efficacy. Unfortunately, limited information is available to aid women in weighing the potential risks of hormonal contraceptive use.Multiple studies in humans and rhesus macaques suggest an association between the use of progesterone-based contraceptives and increased risk of HIV-1 or SIV infection. Although the molecular and cellular mechanisms underlying the effect of hormonal contraceptives on disease progression are not well understood, progesterone and its derivatives have previously been shown to regulate a number of immune mechanisms that may affect HIV-1 pathogenesis. In a recent study, we demonstrated that women using progesterone- based contraceptives exhibit accelerated disease progression and increased risk of succumbing to the disease compared to women using intrauterine devices. Furthermore, our recently obtained in vitro data indicate that medroxy-progesterone, the active component of DMPA, suppresses the function of T cells to a greater extent than progesterone alone. Based on the available evidence, we hypothesize that progesterone- based hormonal contraceptives exacerbate the effect of HIV-1 infection by suppressing antigen-specific cellular and humoral immune responses to HIV-1 and other pathogens via direct and indirect mechanisms. Diminished immune control of HIV-1 proliferation at the acute and chronic phases of infection leads to accelerated depletion of memory CD4+ T cells in lymphoid tissues, deterioration of mucosal barrier function, decreased production of specific IgA,and increased absorption of microbial products to the systemic compartment where they contribute to the chronic activation and death of CD4+ T cells. These hypotheses will be tested in four specific aims addressing the effect of progeterone-based contraceptives on viral load, viral shedding in the genital tract, functional activity of T and B cells, and antibody-dependent cell-mediated virus inhibition. Understanding the effect of hormonal contraception on HIV-1 infection is an important issue with potentially large implications for public health policy. RELEVANCE (See instructions): The effect of progesterone-based contraceptives on the course of HIV-1 infection and immune responses to HIV-1 and other co-infecting pathogens represents an important and under-investigated women's health- specific issue with potentially large implications for public health policy. Any contraception that hastens the progression to AIDS or increases the shedding of HIV-1 in the female genital tract could impact patients' health, survival, spread of the virus in population, and overall program costs.